A. Field of the Invention
The invention relates to an apparatus for making microcapsules, encapsulating pharmaceutical compounds in microcapsules, microcapsules, microcapsule encapsulated pharmaceutical compositions and products, and methods of using the same.
B. Description of the Related Art
Many drugs and enzymes (e.g. cytotoxins or bioactive compounds) cannot be injected intravenously. Others can be injected, but rapidly degrade before reaching the target tissue. Some drugs and enzymes are cleared from the blood by the liver or kidneys so quickly that their biological half-life is too short to be of therapeutic value. Still other drugs are insoluble in aqueous solutions. Since intravenous injection in hydrocarbon solvents is not well tolerated by patients, such drugs are difficult to administer.
These limitations can be overcome by encapsulating the drugs inside small spheres or capsules which can be transported in the blood to the target and which can then release the drug directly to the target by diffusion. Properly designed microcapsules can provide unique methods of direct delivery by injection, nasal inhalation and dermal administration for sustained release of important bioactive drugs.
Solid matrix microspheres may also be used for transporting adsorbed drugs within the matrix. For instance, U.S. Pat. No. 4,492,720 to Mosier disclosed methods for making microspheres to deliver chemotherapeutic drugs (including Cis-Platinum) to vascularized tumors. This method of preparing microspheres is accomplished by liquid encapsulation and solid-phase entrapment wherein the water-soluble drug is dispersed in a solid matrix material. The method involves dissolving the aqueous drug and the matrix material in an organic solvent, in which they are mutually soluble, then dispersing this mixture in a second organic solvent to form an emulsion that is stable enough for intravascular injection.
Other solid-matrix approaches have utilized copolymers such as polyvinyl chloride/acrylonitrile dissolved initially in organic solvents to form microparticles containing aqueous enzyme solutions. U.S. Pat. No. 3,639,306 to Sternberg et al. discloses a method of making anisotropic polymer particles having a sponge-like inner support structure comprising large and small void spaces and an outer, microporous polymer film barrier. A multiple-step batch process is used which entails removal of the organic solvents used to dissolve the polymers prior to addition of aqueous components.
Solid-matrix microspheres, however, are often not perfect spheres thereby limiting the packing density. Additionally, many drugs cannot be trapped or adsorbed in these systems at effective concentrations and drug-release rates are typically cyclic due to higher diffusion rates from the surface than from the matrix core.
Microcapsules may provide encapsulation of higher concentrations and improved drug-release rates. "Microcapsule", as used herein, is a general term which can include any spherical liquid-filled microscopic vesicle surrounded by a semipermeable outer membrane, including, micelles, inverted micelles, bilayer vesicles, and multi-lamellar (multilayered) microcapsules which comprise at least two layers, one of which is innermost and is substantially completely enclosed within the other.
The size and shape of the microcapsules is critical. Microcapsule distribution and drug delivery behavior in the tissues is very sensitive to these parameters. Typically, microcapsules of roughly 1-20 micron diameter are optimum for intravenous administration, whereas, 30-300 micron diameter microcapsules are used for intraarterial delivery and 300 micron or greater for intraperitoneal administration.
Certain current methods of forming microcapsules (such as liposomes) are based on chemical characteristics of certain phospholipids that self-assemble into bilayers when dispersed in an excess of water. Most liposomes carry pharmaceuticals dissolved in the entrapped water. Drugs that are insoluble or that have only limited solubility in aqueous solvents pose problems for incorporation into liposomes. Such organic-soluble drugs are usually limited in liposomal formulations to those that bind inside the hydrophobic region of the liposome bilayer. Some drugs are so insoluble that they do not associate with the bilayer and, therefore, have very low encapsulation efficiencies. Certain liposomal drug formulations, including anti-tumor liposomes containing dexorubicin [Gabizion et al. 1992] or muramyltripeptide have been studied extensively in clinical trials. Many conventional therapeutic liposome microcapsules have natural phospholipid outer skins (usually in combination with cholesterol and fatty amine) and therefore are subject to elimination by immune cells. Other conventional methods use sialic acid and other coatings on the lipid bilayer to mask the liposomes from detection by the scavenging immune cells in the reticuloendothelial system (RES).
Conventional methods of forming microcapsules are based on liquid--liquid dispersions of aqueous drugs and organic solvents. The dispersion methods often require emulsification of the aqueous phase into organic carrier solutions by shear, bubbling or sonication. These methods typically produce water-in-oil (W/O) type liposomes, for which a second requisite step is the removal of the organic solvent (typically by evaporation) to form reverse-phase evaporation vesicles or stable plurilamellar vesicles. The size distribution for these vesicles is quite heterogeneous.
These methods are limited because the density-driven phase separation results in the need to use multi-step, batch processing including mechanical mixing and solvent evaporation phases. Each batch step suffers losses which reduce overall efficiencies. Typically, in order to generate multilamellar vesicles, film casting with organic solvents, hydration and sizing using filtration through inert membrane filters is required [Talsma and Crommelin 1992]. Sophisticated, multi-step emulsion technology is required and yields of uniform type and size are often very low.
For instance, U.S. Pat. No. 4,855,090 to Wallach, discloses a method of making a multilamellar lipid vesicle by blending an aqueous phase and a nonaqueous lipophilic phase using a high shear producing apparatus. The lipophilic phase is maintained at a high temperature (above the melting point of the lipid components) and is combined with an excess of the aqueous phase, which is also maintained at a high temperature. U.S. Pat. No. 5,032,457 to Wallach discloses a paucilamellar lipid vesicle and method of making paucilamellar lipid vesicles (PLV). The method comprises combining a nonaqueous lipophilic phase with an aqueous phase at high temperatures and high shear mixing conditions, wherein the PLVs are rapidly formed in a single step process. U.S. Pat. No. 4,501,728 to Geho et al. discloses the encapsulation of one or more drugs or other substances within a liposome covered with a sialic acid residue for masking the surface of the membrane from scavenging cells of the body utilizing techniques known for the production of liposomes. In one embodiment, additional tissue specific constituents are added to the surface of the liposome which cause the liposome thusly treated to be attracted to specific tissues. Similarly, U.S. Pat. No. 5,013,556 to Woodle et al. provided methods for making liposomes with enhanced circulation times. Liposomes created by this method contain 1-20 mole % of an amphipathic lipid derivatized with a polyalkylether (such as phosphatidyl ethanolamine derivatized with polyethyleneglycol). U.S. Pat. No. 5,225,212 to Martin et al. discloses a liposome composition for extended release of a therapeutic compound into the bloodstream, the liposomes being composed of vesicle-forming lipids derivatized with a hydrophilic polymer, wherein the liposome composition is used for extending the period of release of a therapeutic compound such as a polypeptide, injected within the body. Formulations of "stealth" liposomes have been made with lipids that are less detectable by immune cells in an attempt to avoid phagocytosis [Allen et al. 1992]. Still other modifications of lipids (i.e., neutral glycolipids) may be affected in order to produce anti-viral formulations (U.S. Pat. No. 5,192,551 to Willoughby et al. 1993). However, new types of microcapsules are needed to exploit the various unique applications of this type of drug delivery.
Processes and devices are needed for forming spherical multilamellar microcapsules having alternating hydrophilic and hydrophobic liquid layers, surrounded by flexible, semi-permeable hydrophobic or hydrophilic outer membranes which can be tailored specifically to control the diffusion rate. In particular, devices for making such microcapsules are needed which do not rely on batch processes involving mechanical mixing and solvent evaporation phases. Moreover, there is clearly a need for methods, devices, and compositions which allow for larger and somewhat uniformly sized microcapsules which have the ability to carry larger amounts of drug and/or more than one drug within a semi-permeable outer membrane, possibly dissolved in different solvent phases within the outer membrane. Such improved microcapsules would be particularly useful in the delivery of pharmaceutical compositions.